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Protocol Apatinib for Advanced Osteosarcoma After Protocol Apatinib for Advanced Osteosarcoma after Failure of Standard Multimodal Therapy: an open label phase 2 clinical trial 1.0 Abstract The prognosis of patients with recurrent or refractory osteosarcoma remains poor, with 5-year overall survival rates around 20%. Given the continued poor prognosis in this group of patients, novel treatment strategies are needed. There are no standard chemotherapeutic agents or targeted therapies proven to prolong survival in recurrent osteosarcoma. Apatinib, also known as YN968D1, is a tyrosine kinase inhibitor that selectively inhibits the vascular endothelial growth factor receptor-2 (VEGFR2, also known as KDR). It is an orally bioavailable, small molecule agent which is thought to inhibit angiogenesis in cancer cells; specifically, apatinib inhibits VEGF-mediated endothelial cell migration and proliferation thus blocking new blood vessel formation in tumor tissue. This agent also mildly inhibits c-Kit and c-SRC tyrosine kinases. Pre-clinical data suggest that apatinib may have anti-tumor activity in osteosarcoma. In this Phase 2 study, eligible patients between the ages of more than 16 years with unresected, recurrent or refractory osteosarcoma will receive apaptinib tablets administered daily. Progression free survival and response to therapy will be assessed. In addition, the tolerability and quality of life will be evaluated. 2.0 Experimental Design Schema 3.0 Goals and Objectives (Scientific Aims) 3.1 Primary Aims 1.1.1 To estimate the objective response rate (ORR) at 3 month and progression free survival rate (PFS) at 4 month in patients with recurrent osteosarcoma who are administered apatinib therapy daily. 3.2 Secondary Aims 3.2.1 To estimate the overall survival rate (OS), clinical benefit rate (CBR) at 6 month, duration of response(DOR) in patients with recurrent osteosarcoma who are administered apatinib therapy daily. 3.2.2 To assess the feasibility and toxicity profile of apatinib in patients with recurrent or refractory osteosarcoma, pain improvement and life quality score. 4.0 Background 4.1 Introduction/Rationale for Development The outcome of patients with newly diagnosed, localized osteosarcoma improved following the addition of multi-agent chemotherapy to complete surgical resection [1,2]. Current results in contemporary cooperative group studies reveal 5-year event-free survival (EFS) ranging between 50-75%. [1,2] Cisplatin and doxorubicin are the most active agents, and standard chemotherapy includes the use of these two agents alone or in combination with high-dose methotrexate and/or ifosfamide [2,3,6]. The prognosis is poor for the 30-40% of patients who develop recurrent disease [3]. as well as for those with clinically detectable metastases at the time of initial diagnosis with 2-year survival rates of 20-30% [6,10]. The aggregate EFS for patients with recurrent osteosarcoma enrolled on seven closed Phase 2 studies from the Children’s Oncology Group (COG) or its predecessor groups is poor, with an overall 12% EFS at 4 months [5,7,8,9,10]. Due to the lack of progress seen in treatment of osteosarcoma over the past 25 years and overall poor prognosis for children, adolescents and young adults with recurrent or refractory osteosarcoma, novel treatment strategies are needed. The study of oncogenesis and pathobiological behavior of osteosarcoma told us that new blood vessel formation (angiogenesis) is fundamental to tumor growth, invasion, and metastatic dissemination [23]. Several groups have evaluated tumor microvessel density and outcome in osteosarcoma. Expression of VEGF has been suggested as a means of evaluating the prognostic importance of angiogenesis in osteosarcoma [17,18,19]. Monotherapy with second-generation broad-spectrum VEGF receptor tyrosine kinase inhibitors (TKIs) in sarcoma has now become an area of active research and application beyond gastrointestinal stromal tumors (GISTs) [4,14]. Within all of those preclinical experiments and clinical trials [16,18,20], the milestone of the treatment on advanced osteosarcoma should count on the application of anti-angiogenesis TKIs sorafenib on refractory cases from the Italian Sarcoma Group [20,22], which officially raised the 6-month progression-free survival (PFS) from <30-46% for the first time. However, things had seemed not to change as dramatically as was expected since then. Apatinib, also known as YN968D1, is a tyrosine kinase inhibitor that selectively inhibits the vascular endothelial growth factor receptor-2 (VEGFR2, also known as KDR)(Fig. 4.1.1). It is an orally bioavailable, small molecule agent which is thought to inhibit angiogenesis in cancer cells; specifically apatinib inhibits VEGF-mediated endothelial cell migration and proliferation thus blocking new blood vessel formation in tumor tissue. This agent also mildly inhibits c-Kit and c-SRC tyrosine kinases. Fig.4.1.1 Schematic illustration of the possible mechanism of apatinib as the inhibitor of VEGFR-2. Apatinib was approved and launched in People’s Republic of China in 2014 as a subsequent-line treatment for patients with advanced gastric cancer (AGC). In addition, it is also currently undergoing Phase II/III clinical trials in People’s Republic of China for the treatment of many cancer types, such as non-small-cell lung cancer (NSCLC) [24], breast cancer, and hepatocellular carcinoma. These clinical trials demonstrate that apatinib has potential antitumor activity across a broad range of advanced solid tumors. Compared with other TKIs focused on anti-angiogenesis, Apatinib is more effective on VEGFR2 (Table.4.1.1). Table 4.1.1 Comparation of IC 50 in different TKIs target IC50(nM) Apatinib Sorafenib Sunitinib Pazopanib VEGFR-1 70 - 2 10 VEGFR-2 2 90 10 30 VEGFR-3 - - 17 47 PDGFR-b 537 - 8 84 c-kit 420 68 - 74 FGFR-1 >10000 580 - - FLT-3 - 58 - - 4.2 Preclinical Studies Several basic studies have been dedicated to the antitumor activity of apatinib in vitro and in vivo. In vitro, apatinib potently suppressed the kinase activities of VEGFR-2, c-Kit, and c-Src, and inhibited cellular phosphorylation of VEGFR-2, c-Kit, and PDGFRb. Apatinib could also effectively inhibit proliferation, migration, and tube formation of human umbilical vein endothelial cells induced by fetal bovine serum, and block the budding of rat aortic ring. What’s more, apatinib has also been demonstrated effective in several kinds of human cancers in vivo(Table 4.2.1). Encouraged by the remarkable inhibitory activity against VEGFR-2 tyrosine kinase in vitro, they further performed the investigation of the potential antitumor effect of apatinib in vivo. The results demonstrated that apatinib showed antitumor efficacy in vivo when administrated alone or in combination with chemotherapy against a variety of established tumor xenografts with good tolerance[24]. To date, the outcome of cancer chemotherapy still encounters two major challenges: nonspecific targets and multidrug resistance (MDR). In fact, more than 90% of patients with malignant tumors die of MDR. Apatinib could also reverse cancer MDR mediated by MDR protein 1 (ABCB1), MDR-associated protein 1 (MARP1), and breast cancer resistant protein (BCRP) through inhibiting their transport function as well[24]. Thus, apatinib may be useful in overcoming MDR to other conventional antineoplastic drugs. Table 4.2.1 Apatinib is effective in several kinds human cancers in mice. pharmacodynamic model Dose(mg/kg) inhibitory effect(%) Gastric cancer SCG-7901 50-200 39.3-80.7 Colon cancer Ls174t 50-200 20.3-83.7 Colon cancer HCT-116 50-200 41-81.2 Colon cancer HT-29 50-200 37.2-74.5 NSCLC A549 50-200 29.2-72.8 NSCLC NCI-H460 100, 200 43.1-78.8 Hepatic cancer H22 50-200 43.3-84.7 Sarcoma S180 50-200 60.3-69.9 4.3 Apatinib in Published Clinical Trials Apatinib has been administered to a total of 338 patients with gastric cancer, non-small cell lung cancer or breast cancer in 3 clinical trials. In a randomized, placebo-controlled, parallel-arm Phase III trial (NCT00970138), Li et al evaluated apatinib as a subsequent-line therapy for patients with histologically confirmed gastric cancer. In the trial, 144 enrolled patients were divided into three groups: placebo (group A), 850 mg of apatinib qd (group B), and apatinib 425 mg bid (group C). Progression-free survival (PFS) was the primary end point. Secondary end points included DCR, objective response rate, overall survival, and quality of life. The outcomes demonstrated that the median progression-free survival for groups A, B, and C was 1.40 months, 3.67 months, and 3.20 months, respectively. OS for groups A, B, and C was 2.50 months, 4.83 months, and 4.27 months, respectively. There were statistically significant differences between the apatinib groups and the placebo group in PFS and overall survival (P<0.001). But, there was no significant difference between apatinib 425 mg bid vs 850 mg qd (hazard ratio [HR]:1.22, P<0.551). These results illustrated that apatinib showed improved PFS and overall survival in heavily pretreated patients who had experienced treatment failure with two or more chemotherapy regimens. A prospective, open-label, Phase II trial by Hu et al aimed to evaluate the efficacy and safety of apatinib in heavily pretreated patients with metastatic non-triple-negative breast cancer (TNBC) (NCT01176669). In the trial, after the optimum dose level of 500 mg/day was recommended by Phase IIa, a Phase IIb study of 59 patients with metastatic TNBC was activated, with the endpoint PFS. The outcomes were reported that mPFS and mOS were 3.3 months and 10.6 months, respectively. In the 56 evaluable patients, overall response and clinical benefit rates were 10.7% and 25.0%, respectively. As for adverse events, the most common grade 3/4 hematologic toxicities were thrombocytopenia (13.6%), leukopenia (6.8%), neutropenia (3.4%), and anemia (1.7%). The most frequent grade 3/4 nonhematologic toxicities were hand–foot syndrome, proteinuria, hypertension, and increased alanine aminotransferase.
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